It started with a slight twitch. Steve and Gay Grossman both noticed it in their daughter Lilly in 1998, when she was just one-and-a-half years old. By the time she was four, the twitches had grown into full-blown muscle tremors. They wracked her whole body at night and were painful enough to wake her up.

The family stopped sleeping properly. Lilly would wake up, shaking and crying, as often as 20 or 30 times a night. During the worst bouts, Steve and Gay took shifts to console her, one staying with her until two in the morning and the other taking over from there. “I can’t describe what it’s like to care for a baby, a young child, who’s crying and shaking all night,” says Steve.

The Grossmans have dealt with this for the last 13 years and, if anything, Lilly’s tremors became more frequent and more severe. They eventually started happening during the day. She developed muscle weakness, poor coordination and balance problems. She had to use a walker until middle-school and a motorised wheelchair thereafter. She was often very tired.

Then, in the summer of 2012, the tremors stopped. For 18 days, Lilly slept soundly through the night. So did Steve and Gay. “We had dreams again,” he says. “We had forgotten what that was like.”

This U-turn in Lilly’s fortunes was the result of a study called IDIOM, led by the father-and-daughter team of Eric and Sarah Topol at the Scripps Translational Science Institute in La Jolla, California. IDIOM stands for Idiopathic Diseases of Man—that is, “serious, rare and perplexing health conditions that defy a diagnosis or are unresponsive to standard treatments”. In other words, whatever Lilly had.

The Scripps team sequenced Lilly, Steve and Gay’s complete genomes. Amidst the morass of As, Gs, Cs and Ts, they identified the likely causes of Lilly’s mystery condition—three mutations in two different genes. One of these pointed the way to a potential treatment—a drug called Diamox that had helped another family with a fault in one of the same genes. When Lilly tried it, she gained a few weeks of sound tremor-free sleep.

“Whole-genome sequencing can change lives and maybe save some,” says Steve. “It changed ours.” It was no miracle—the tremors have returned to a lesser extent than before, and the team are pursuing new leads. But Steve and Gay never expected The Answer. They didn’t anticipate an easy cure. Genomics gave them something arguably more important—hope. It turned the nameless, unknowable ailment that had stolen years of sleep from their daughter into something tangible—a condition with a cause that can eventually be addressed. And it bought them time with Lilly.

Lilly Grossman, 3rd grade, courtesy of Steve & Gay Grossman.

Two – Not Knowing

Lilly’s life has been defined by both the condition that restricts her choices, and the smarts, tools and support that allow her to escape those restrictions. Gay recalls, “Ever since Lilly was really small, she’d be up most of the night and in the morning, I’d say, “Why don’t you stay with me and relax?” And she would just cry and cry to go to school. She always wanted to be doing what the other kids were doing.”

Schools can make many children feel isolated or different, but they have always been great equalisers for Lilly. Her weak muscles and sensitivity to warm temperatures meant that, at home, she missed out when other kids played outside. At school, everyone sat and so did she. She got to use a brain that, tiredness aside, has stayed untouched by her physical symptoms. “She’s a regular teenager—smart, sarcastic, funny—and she has a grade point average of 3.5,” says Steve.

Lilly became a technophile out of necessity. Since pens and books are painful to hold, she has used laptops since kindergarten. Her voice tires easily and she hates it when people talk to her like she’s deaf or infirm; when she got her first cellphone and started sending texts, her social life blossomed. She was always good at maths but since drawing figures was taxing, she gravitated towards English and reading-heavy subjects. She now fancies herself a writer, penning pieces for her school newspaper, posts on her blog, and an online book about disability called Through My Eyes.

Through all of this, Steve and Gay have worked tirelessly to support her. She designs a stationery line called Letters from Lilly and spends her day “arguing with insurance companies and school bureaucracies”. He works at a software company with links to aerospace and defence and sources all the technology that allows his daughter to live as independently as possible. When it came time to tell Lilly’s story, Gay wrote three pages of text. Steve prepared a PowerPoint presentation.

For the longest time, the duo were bedevilled by uncertainty about Lilly’s condition and the belief that her time was slowly running out. Doctors initially diagnosed Lilly with cerebral palsy, but that wasn’t it. Next came a diagnosis of glutaric aciduria, leading to a modified diet and a lot of support groups. That wasn’t it either. The next guess was the heartbreaker: some kind of mitochondrial disease. These disorders affect the tiny bean-shaped batteries that power our cells. They vary a lot, but given the harsh and relentless nature of Lilly’s symptoms, Steve and Gay were worried. “The life expectancy for a teenager isn’t so great,” he recalls.

Printed out, Lilly’s medical records take up two four-inch binders. She’s had MRI scans, blood draws, spinal taps, skin biopsies, nerve biopsies, and a muscle biopsy. The tests hinted at a few depleted nutrients that could be fixed by supplements, but for the most part, they said the same thing: Lilly seemed normal. “We’ve been from world-class people to alternative quacks,” says Steve. No one could offer them the surety of a true diagnosis, much less a suitable treatment.

“Every birthday was a hard one—missed milestones and another reminder that we still didn’t know what’s wrong with her,” says Gay. When would the sand eventually run out? This year? The next one? “When you don’t know what you’re dealing with, and you’re up all night with your kid crying and shaking like crazy, you think: Does anyone even remember this is going on? Nobody knew what to do with us.”

Lilly, on her first easter in La Jolla.

Three –The Study

In 2005, when Lilly was eight, the family moved from Cleveland, Ohio to the more stable climate of La Jolla, California. “If things weren’t going to get better, we thought: At least, let’s go somewhere nice, where we can be outside,” says Steve. San Diego was also a thriving hub of medical research, including many scientists who worked on mitochondrial disease. Steve and Gay dreamed of a lucky random encounter.

For years, they were stuck in a holding pattern. Then, on June 16, 2011, Gay saw the following headline while browsing through NPR: Genome Maps Solve Medical Mystery For Calif. Twins. The article told the story of Alexis and Noah Beery—two twins of Lilly’s age who also had a long history of motor problems. They were also misdiagnosed with cerebral palsy before someone correctly worked out that they had a genetic disorder called dopa-responsive dystonia (DRD). It’s caused by low levels of dopamine—a chemical that carries signals between nerve cells. The twins had been taking a drug that boosts dopamine levels, which initially seemed to control their symptoms.

As they got older, Noah started getting hand tremors and his attention suffered, while Alexis developed breathing problems so severe that she needed daily adrenaline shots to stop herself from suffocating. Their parents, Retta and Joe, turned to scientists at Baylor College of Medicine, who sequenced Alexis and Noah’s full genomes. They identified a mutation in a gene called SPR, which depletes another brain chemical called serotonin. The twins started taking serotonin-boosting drugs too, and their health greatly improved.

It was the success story that the Grossmans had long anticipated. They knew that whole-genome sequencing was a possibility, and had been waiting for it to become readily available. When Gay read about the Beery twins, she thought, “Wow, this is really here.”

Good news: the Beerys lived in San Diego. Lilly met the twins, while Retta and Gay became good friends. Better news: the Beerys’ doctor was Jennifer Friedman from University of California, San Diego, who was also handling Lilly’s case. But Friedman has already talked to the Baylor researchers and found that they needed a sibling for their study. Alexis and Noah had each other. Lilly was an only child.

Then, Steve and Gay learned about the IDIOM study through a friend of Retta’s. It seemed perfect. Here was a world-class facility, practically on their doorstep, trying to solve medical mysteries of the kind that afflicted Lilly. And they wanted to sequence a trio: dad, mum and child.

Gay put together a bright pink binder, emblazoned with photos of Lilly, and full of her writing, test scores, and a DVD of all her medical records. She sent it to Sarah Topol. “I wanted to make sure that they would never forget her,” she says. She needn’t have worried; Lilly fit IDIOM’s criteria perfectly. “Her symptoms looked likely to have genetic underpinnings,” says Nicholas Schork from Scripps.

Lilly became the first child to be enrolled into IDIOM, but she kept measured expectations. On her blog, she wrote, “Scripps will keep my records for twenty years so that if they find out any new information, they will try again. And they will keep trying until they figure me out.”

The family has a mantra: It’s a marathon not a sprint. They were battle-hardened from a long road of possible fixes and disappointments. “We thought: This is great but it’s probably just going to be another data point that we add to the binder,” says Steve.“Lilly’s already had a lot of bad news in her life,” says Gay. “Her biggest fear was that we wouldn’t find anything. Not knowing would be the worst thing.”

Gay and Lilly Grossman volunteer with National Charity League, San Diego Chapter.

Four – Knowing

The IDIOM team took blood from the three Grossmans and sequenced their complete genomes, as well as their exomes—just the bits of DNA that code for proteins. (Lilly explains the process very clearly on her blog.) By comparing Lilly’s sequences against those of her parents, and cross-referencing any differences against what was known about the associated genes, the team identified just two of interest. “The list of candidates was already quite short, and none of the others made sense,” says Ali Torkamani, who led the analysis.

The first gene—ADCY5—influences dopamine’s ability to pass signals between neurons. It’s particularly active in a brain region called the striatum, which helps to plan and coordinate movements. The second—DOCK3—influences the movement of molecules within the neurons that control our movements. Mice that lack this gene entirely have uncoordinated movements and weak muscles.

Lilly had inherited a mutation in DOCK3 from Gay, but she also had one unique ‘point mutation’ in both ADCY5 and DOCK3—a single altered DNA letter that was absent from either of her parents’ versions. The team had expected as much, since neither Steve nor Gay had any of Lilly’s symptoms. Her genetic quirks, whatever they were, were most likely unique to her, rather than family heirlooms.

The team suspects that ADCY5 accounts for Lilly’s shaking, while DOCK3 influences her balance and muscle weakness. It seems that she was born with extraordinary bad luck—a double-whammy of fresh mutations in two separate genes that conspired to produce her unique constellation of problems. “That doesn’t discount other genes having a role,” says Schork. “It’s just that these two seem to be the most logical candidates.”

They sent their results to Friedman.

By this time, a different team of geneticists at the University of Washington had identified another family with an ADCY5 mutation, where the affected members shared some of Lilly’s symptoms. They had tested a couple of different drugs and one—Diamox—had helped some of them but not others.

Diamox interferes with an enzyme called carbonic anhydrase, which helps to maintain the right pH balance in the blood. In cases where blood is too alkaline, the drug acidifies it. There’s no particular reason why it should help people with faults in ADCY5, but it has a history of being useful for movement disorders. That’s why the Seattle team tried it, and their success intrigued Friedman. She saw two options. The more “biologically pleasing” one would have been to design treatments that directly addressed the problems caused by Lilly’s defective genes. The other was to try what worked before, even without a clear rationale. Friedman considered both strategies and recommended the latter.

It was August 2012, and the Grossmans were about to go on holiday when Friedman emailed them about the results. (Steve thinks she called. Gay says she emailed. Steve taps out.) After years of nothing, they found themselves oddly unprepared for a test result that actually had a result. They went to see Friedman by themselves, and she spent two hours explaining everything. There were two genes. One suggested a possible treatment. She wanted to try it. They had options.

After the Grossmans left the meeting, they drove home in silence. Steve broke it.

“Did you hear her say ‘normal life expectancy’?”

Five – The Marathon

Lilly getting ready for homecoming dance. By Steve & Gay Grossman

“I am so happy that my genome didn’t come back all normal and say nothing is wrong,” Lilly wrote. “These next few months will be very interesting.”

She started on Diamox two weeks later. The first night was horrific. She shook and cried more than ever, but after she acclimatised to the drug, she slept soundly for 18 consecutive nights. She cut down on other medications and became more alert at school. The whole family got a boost. “When you have a long stint of all-nighters, you drop into a haze,” says Steve. “I feel smarter again.”

But this was no miracle cure. The tremors eventually returned. “The response waxes and wanes, and it’s not 100 percent clear whether the treatment is effective or not,” says Torkamani. But the Grossmans are adamant that Lilly’s dramatic improvement was no placebo effect. She still shakes herself awake, but less frequently or severely than before. The all-nighters are a thing of the past. She feels better during the day, and her platter of anti-seizure medicines and sedatives has been replaced by a small and benign set of supplements.“At least we know we found something that works,” says Steve. “Now, we just need to know how to make it work all the time.”

The knowledge is what matters, especially the fact that Lilly does not have mitochondrial disease. “We just celebrated her 16th birthday. That was the first one where we’ve known that Lilly will be here on her next one,” says Gay. “That alone was worth the sequencing. It bought us time. We always thought there wasn’t much time.” Before, they paid lip-service to the future. Now, they’re looking at colleges, jobs, and organisations that can help people with physical disabilities to transition towards independent adult life.

The Scripps team is now trying to better understand the ADCY5 variant that Lilly has, and to see if they can identify a treatment that directly addresses the problems caused by this faulty gene. Meanwhile, Steve and Gay are talking to Friedman about tweaking Lilly’s medications. Just last Friday, they decided to try a stronger dose of Diamox; Lilly only got up three times on Saturday night.

Steve and Gay are collecting as much data as possible. They use an iPad app designed to measure contractions in pregnant women to record the length and strength of Lilly’s shaking bouts. In the morning, Gay emails the data to the IDIOM team. Meanwhile, Steve’s checking out different accelerometers that Lilly could wear to collect the data automatically. “If we try a new drug and we get a, say, 2% drop in shaking one night, we can act on that,” he says.

Whole-genome sequencing doesn’t provide easy answers. For every prominent success story, like the Beery twins or Nicholas Volker, there will be tales where the path from genome to treatment meanders and backtracks. In another case, the IDIOM team identified a genetic variant in a different patient that suggested a potential treatment, but hit an impasse when the child’s physician disagreed.

Lilly had the benefit of well-educated and realistic parents, and a doctor who was savvy about genomics. Many scientists have debated how genetic results should be returned to patients but the Scripps team has a simple solution: They rely on “physician champions” like Friedman. It’s their call how to convey the results and factor them into any treatment plans. That takes time and genetics expertise, and many doctors are short on both.

“The public perception is that you send your genome for sequencing and you come back with an answer, like your cholesterol level,” says Friedman. “The reality is that there’s ambiguity in the results and their interpretation. It’s an iterative process that has to be re-examined year after year. It’s not a crystal ball; it’s a fuzzy vision of the future.”

Cinnamon Bloss, a clinical psychologist at Scripps who worked with the Grossmans, adds, “This story highlights how promising whole-genome sequencing is, but also the difficulties that have yet to be overcome. Sequencing is getting cheaper and more powerful, but the social support that it relies upon is not easily scalable. Many stars must align. The Grossmans understand that. “Treatments aren’t going to be instantaneous or 100 percent, but they’re hope,” says Steve. “We gained hope. And the more data we have, the better position we’ll be in to figure this out.”

It’s a marathon, not a sprint.

Six – Epilogue

One Friday, last September, Steve and Gay took Lilly to meet the Scripps team. She had met Bloss and Sarah Topol, but the rest were faceless names looking out for her from afar. She brought homemade, individually-wrapped chocolates and a thank-you note for every member of the team. Here is what it said:

Dear Scientists,

Thank you for what you do every day. Without you, I would still be shaking every night and be exhausted during the day. Now that I’m sleeping, I no longer have to wear socks when I sleep for fear of scratching my legs with my toenails when I shake.

I look forward to being able to sleepover at my friends’ houses, instead of always having to invite them over because of my shaking.

School will be so much easier now that I’m sleeping as well. My family and I can’t thank you enough!

Love,

Lilly.

Related

51 thoughts on ““We Gained Hope.” The Story of Lilly Grossman’s Genome”

A great article and a fine example of drug repurposing. Who knew that a carbonic anhydrase inhibitor could be so unpredictably useful in a rare and important disorder. This story is also encouraging since there’s a lot of carbonic anhydrase inhibitors around for conditions like glaucoma. So even if one doesn’t work you could try another.

Damn you, Ed. I think I must have a bit of grit or something in my eye.

Steve, Gay, and especially Lilly, you talk about having gained hope. But a story like yours, and the amazing way that you have faced it – with courage, honesty and humour – gives hope to us all. May you ever stay strong, and may you one day find the victorious finishing line to your marathon.

Wow! I don’t recall being so moved by NERS before. Lilly sounds extraordinary, and I hope you will give us follow-ups (will also check her blog). Now ifyou’ll excuse me, I seem to have some dust in my eye…

With the love and support the three of you give to each other you will find answers with the love and support of all the brilliant minds who are now on your courageous team. You know I honor you and love the three of you for your valor, honesty, loyalty, and commitment.

A marvelous piece. The combination of your description of the progress in scientific research with how it relates to actually treating and helping real humans is seamless. Every time I think you can’t outdo yourself…you surprise me, Ed. Thank you Lilly, Gay and Steve for welcoming Ed (and all of his readers) into your story.

Ed – thank you for focusing your attention on one of the many inspiring stories of courage demonstrated by ordinary people who have to deal with rare – in Lilly’s case, one of the rarest – diseases.

Rare Disease Day 2013 has just come around, and the next worldwide Rare Disease Day will be February 28, 2014. I will be more than happy to help you find another fantastic story to report by next year. Please do!

It is a marathon, not a sprint – for the Grossmans, and for close to one family in twenty, all 7,000+ rare conditions combined. Even when there is a name to your disease, even when there is a treatment identified, alone we are still rare. Together, we are strong. Thanks to this story you have reported, among so many out there, we collectively can continue to hope – and to prevail.

As a scientist studying a number of rare diseases, I can assure you that my physician and scientist research colleagues and I are absolutely emotionally involved in this work. We show it in different ways. These back stories are also moving.

Absolutely fabulous article, and something that I plan to point friends and family members to when they ask about why I chose to study genetics and what that can really mean for people’s lives. Best of luck to Lilly, her family, and the team of people standing behind her.

Great story! Those of us who have worked in the field of genomics have an enormous appreciation for what it can do to facilitate human healthcare. It’s so unfortunate that the hope garnered by genome sequencing is appreciated by only a fraction of the medical establishment. The Grossman family and this article are a testament to how many health practitioners today are missing the boat by not taking genomic medicine seriously.

very very interesting, as I to have a rare condition that has not yet been fully comprehended. leaving me waking and startled from excruciating pain that becomes unbearable. The pain threshold has exceeded the limit leaving my trembling and paralized, swelling of the face and brain, from traumatic events, drastically attacking the central nervous system, leaving night tremors in brain and neck, pain is unbearable leaving me crying my eyes out weeping for someone to care enough to help, loss of motor skill and abilities that use to come so very easy leave me paralyzed .

I have know Gay, Steve & Lilly since she was born thru her deceased grandfather,my friend, and feel like they are family. Am so
happy to know Lilly is being helped. May God bless this dear family. Love & Hugs, Jane

HELP!! I have the same issues, and have been to the best motor specialist in the country. The only thing that helps mine at all is a injection of Geidon. I’ll shake myself away up to hundred times a night. My husband sleeps in a different bed because I shake the bed so hard. I also have them in the day time as well. I have to go to the emergency room when they get so severe that I can stand up, or think. I need this done. Where do I start?

I am very happy to have run across this article. I have Familial Periodic Paralysis, a rare genetic condition in which Diamox has been found to improve 50% of cases. I am hoping to be one of them. I started on Diamox in November. It has been a very rocky road, but I’m trying my best to hang in there as it is slowly helping to reduce my paralytic episodes. Thank you for sharing Lilly’s story, and I wish her the very best!

We adopted our daughter. She has microcephaly so had a genetic array done. She has a 300,000 base pair deletion on 1q22. But so far is thriving. We found out about a group out of England called Unique. All of this genetic information is so new they try to create a user database with deletions and symptoms.

We don’t know what our daughter’s deletion might mean. She is an amazing 2 year old right now. But we are very thankful for all the scientific work being done.

I remember Steve and gay in college, they were the cutest couple! I had know idea how strong they were too! Lily is a dream child and I know they are stronger everyday due to her strength and fight! Makes me proud to have known these kids in college!

I am so excited to see your smiling face again Lilly and to hear more about your story and to also know that you have such great doctors on your side…you, your mom, and dad have always been and continue to be an inspiration to me about true love and conquering obstacles. I am so happy to hear that you received your gold award and are sleeping better 🙂
Much love. xoxoxo

What a genuine life tale! Just shows you how parents with determination, courage and willingness to go that extra uncharted mile for their kids and trust in modern science can do wonders manhood couldn’t think about a few years ago. Wonderful!

And that letter warmed by heart. Love you Lilly, and stay strong & happy! xxx

What an awesome story of life young lady.. To be where you are now in your struggle to live a better life, is so inspiring.. Not only do you show determination in your life, but also add so much promise and hope for other’swith similar gene mutations. You are so courageous, perhaps one day you will be our nation’s president!!

I went to high school with Gay, and as a teenager she was smart, strong and graceful. Clearly, she maintains those traits and has passed them along to her beautiful daughter! An amazing family and an inspiring story… We can all learn from their resilience and hope.

Lilly,
I am so incredibly happy for you and your family. You are an amazing person and it is about time things start going your way (even if you always laughed at me). Hope this is only the beginning!
Mr. Best

Amazing story of perseverance by two incredible parents and one wonderfully brave and intelligent young woman. California was certainly the right move but still miss you back in Cleveland. May more relief be just around the corner.

Steve,Gay & Beautiful Lilly, Your love & perseverance is a story that all should embrace, we maybe can’t cure all that is different in each of us but we can learn to live better with others thru your story. We miss all of you here in Ohio. Our love & prayers are with you.

As suggested by the title of this wonderful article,sometimes all you need is a little hope when the sadness and exhaustion bites hard. My daughter has a 10 year old non verbal Autistic boy and for the sake of privacy I’ll call him Jake. When I read this heart warming article about Lilly and her courageous and devoted parents, I couldn’t help thinking of what this sort of technology could make possible. After years of all night screaming and a range of other socially challenging traits, Jake has settled down somewhat, but most of his life and that of his parents remains the same. My question is whether this sort of genetic analysis has helped others with Autism (plus unknown genetic problems) and whether this could help us. If so I would love to hear from you, regards John

I read your story and cried. I have a now 16 month old son who was racked with insomnia and like Lilly could only sleep for 20 minutes at a time. He would awaken screaming and in pain. He was put on diamox for what was initially thought to be a venous outflow issue causing increased ICP, we now know this is not the case. But without diamox our poor baby cries, is miserable. With diamox he sleeps, swelling improves, balance improves, weakness improves. As only you know, it is so hard to hear that they don’t know why a drug works or what the cause of the symptoms. We thank god that somehow he was put on a medication that works. Now his team of providers are working to solve the mystery “backwards” (diamox works…. But why and for how long). Everyday is an eternity when you watch your baby suffee

I just said a prayer for her well being and her joy to continue in her life.

My compliments to her parents who have to work extra hard in this life to provide for their daughter both emotionally and physically. Being a caregiver is a tough job. Much harder than most people realize. And, there are plenty of selfish people around who would merely abandon their child to a skilled nursing home….. the heartless, selfish, cold emotion types who only think of themselves. Lilly is so lucky to have high quality parents.

My mother befriended Gay in Cleveland when our son at age two was diagnosed with JRA. We were seeing an alternative physician and getting great results. Lilly became a patient of our doctor but sadly hit more brick walls, no solutions. I remember when the Grossmans’ moved to San Diego. My husband came across this article via Facebook today. I am so moved, tears streaming. Like many of you have commented, how can you not be blown away by these three incredible people, who have held their heads high with persistent fortitude. And God bless the doctors, the researchers who use their brilliance to break new ground. Truly amazing. I will pray for continual improvement in Lilly’s condition.

As a retired clinician for multiple expamples of challenged chilldren, this example of research is indeed encouraging. How grateful I am that we don’t just “give up” to idiocsyncrasy but determine to understand and bring hope and help to unique disfunction. Onward!

Aside from the fact that I can’t stop crying….I need to say that I wish I knew all of you so that I could commend you and HUG you in person. You guys have lived an amazing life; one that has not been easy and you have never given up hope. I am the mother of a disabled adult child and I know the struggle you have been through. Lilly, you are amazing and I can see that you will make giant strides in your future. Mom and Dad…keep it up….she has made you proud and will continue to do so. I look forward to future postings so I can keep up with your progress. Thank you so much for sharing your story.

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Phenomena is a gathering of spirited science writers who take delight in the new, the strange, the beautiful and awe-inspiring details of our world. Phenomena is hosted by National Geographic magazine, which invites you to join the conversation. Follow on Twitter at @natgeoscience.

Ed Yong is an award-winning British science writer. Not Exactly Rocket Science is his hub for talking about the awe-inspiring, beautiful and quirky world of science to as many people as possible.
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